rs13306575

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000433.4(NCF2):c.1183C>T(p.Arg395Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 1,614,072 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R395Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0057 ( 24 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 337 hom. )

Consequence

NCF2
NM_000433.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:9

Conservation

PhyloP100: 1.76

Variant links:

Genes affected

NCF2 (HGNC:7661): (neutrophil cytosolic factor 2) This gene encodes neutrophil cytosolic factor 2, the 67-kilodalton cytosolic subunit of the multi-protein NADPH oxidase complex found in neutrophils. This oxidase produces a burst of superoxide which is delivered to the lumen of the neutrophil phagosome. Mutations in this gene, as well as in other NADPH oxidase subunits, can result in chronic granulomatous disease, a disease that causes recurrent infections by catalase-positive organisms. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2010]

NCF2 links:

SMG7 (HGNC:16792): (SMG7 nonsense mediated mRNA decay factor) This gene encodes a protein that is essential for nonsense-mediated mRNA decay (NMD); a process whereby transcripts with premature termination codons are targeted for rapid degradation by a mRNA decay complex. The mRNA decay complex consists, in part, of this protein along with proteins SMG5 and UPF1. The N-terminal domain of this protein is thought to mediate its association with SMG5 or UPF1 while the C-terminal domain interacts with the mRNA decay complex. This protein may therefore couple changes in UPF1 phosphorylation state to the degradation of NMD-candidate transcripts. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2011]

SMG7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0075665414).

BP6

Variant 1-183563302-G-A is Benign according to our data. Variant chr1-183563302-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-183563302-G-A is described in Lovd as [Likely_benign]. Variant chr1-183563302-G-A is described in Lovd as [Benign]. Variant chr1-183563302-G-A is described in Lovd as [Pathogenic].

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0931 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCF2	NM_000433.4 linkuse as main transcript	c.1183C>T	p.Arg395Trp	missense_variant	13/15	ENST00000367535.8	NP_000424.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCF2	ENST00000367535.8 linkuse as main transcript	c.1183C>T	p.Arg395Trp	missense_variant	13/15	1	NM_000433.4	ENSP00000356505	P1	P19878-1

Frequencies

GnomAD3 genomes

AF:

0.00565

AC:

860

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0331

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0455

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00673

GnomAD3 exomes

AF:

0.0186

AC:

4665

AN:

251332

Hom.:

289

AF XY:

0.0143

AC XY:

1943

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.108

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0449

Gnomad SAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00783

GnomAD4 exome

AF:

0.00418

AC:

6113

AN:

1461790

Hom.:

337

Cov.:

AF XY:

0.00356

AC XY:

2592

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.0955

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0343

Gnomad4 SAS exome

AF:

0.00126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.00462

GnomAD4 genome

AF:

0.00565

AC:

861

AN:

152282

Hom.:

Cov.:

AF XY:

0.00611

AC XY:

455

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00195

Gnomad4 AMR

AF:

0.0330

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0460

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00666

Alfa

AF:

0.00345

Hom.:

Bravo

AF:

0.0107

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0151

AC:

1834

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2

Pathogenic:1Benign:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1999	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 13, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 21, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2019	This variant is associated with the following publications: (PMID: 31180159, 10498624, 29560547, 29454792, 12887891, 23821607, 25795782, 24123366, 10598813, 24163247, 22995991) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

.;.;T;T;T;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.95

D;D;.;D;D;D

MetaRNN

Benign

0.0076

T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.5

.;.;M;M;.;.

MutationTaster

Benign

0.051

A;A;A;A

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-4.1

D;D;D;D;D;D

REVEL

Benign

0.22

Sift

Uncertain

0.0050

D;D;D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;.;.

Polyphen

0.99

.;.;D;D;.;.

Vest4

0.55

MPC

1.0

ClinPred

0.059

GERP RS

4.8

Varity_R

0.66

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over